Summary Targeted drug delivery has been a long-term goal for biomedical science. Of specific interest, are those drugs which exert powerful therapeutic effects but cannot be prominently used due to harmful side- effects during systemic delivery? Bone has become a tissue of specific interest for targeted delivery, due to 1) its unique mineralized structure, distinguishing it from other tissues and 2) leading bone therapeutics such as radiodrug and osteoporosis treatments often have harsh systemic effects. The use of general bone-binding moieties such as bisphosphonates, poly-aspartic acid and tetracycline provides preliminary evidence that localized drug delivery to bone is possible in numerous in vitro studies and in vivo animal models. While a number of therapeutics could be delivered to bone, we have chosen antibiotics for two key reasons: 1) we have an effective drug-binding peptide in hand and 2) bone infections are painful, devastating and far too numerous. During this proposed Phase I research program, we will therefore attempt to use Affinergy's core technology to identify peptides capable of binding bone, to be used as a component in our bifunctional peptide delivery systems. We will then couple these novel bone-binding peptides to antibiotic-binding peptides, which have already demonstrated the ability to bind, retain and release bioactive antibiotics from biomaterial surfaces. Affinergy has developed a generalized approach to creating target-specific modular peptides that bind bioactive agents (drugs, growth factors, cells, etc.) to synthetic surfaces (metals, plastics, polymers, etc.) or tissues. These specifying and grafting biopolymers are termed "interfacial biomaterials" (IFBMs). A bi- functional IFBM has the unique advantages of a) providing high surface binding affinity and specificity, b) assembly using robust chemistry for broad-based applications, and c) offering the capacity to specify a wide range of biologic activities onto a single material or surface. IFBM technology addresses limitations of previous antibiotic coating methods because 1) linker peptides can be attached to potentially any tissue or medical implant surface during a short incubation at point of care, and 2) new IFBMs designed to bind multiple antibiotics, would allow clinicians to choose the appropriate antibiotic for a specific clinical situation. Our proposed goal is to therefore generate bifunctional peptides, capable of non-covalently linking antibiotics to bone, satisfying the unmet need for localized antibiotic delivery to bone tissues. After successfully accomplishing this goal we would target other therapeutics, such as hematopoietic agents, osteoporosis inhibitors and osteogenic factors for localized bone delivery. We feel the aims presented here represent a proof-of-principle research program, which would be expanded to include new antibiotics and commercialization strategies during a subsequent Phase II funding period. PUBLIC HEALTH RELEVANCE: Osteomyelitis is a challenging infection of bone tissue, most often caused by a contaminated open fracture site after trauma, or as a nosocomial infection during an orthopedic surgical procedure. While a number of therapeutics could be delivered to bone, we have chosen antibiotics as our initial target for two key reasons: 1) we have an effective drug-binding peptide in hand and 2) bone infections are painful, devastating and far too numerous. Affinergy has developed a generalized approach to creating target-specific modular peptides that bind bioactive agents (drugs, growth factors, cells, etc.) to synthetic surfaces (metals, plastics, polymers, etc.) or tissues. Our proposed goal is to therefore use our platform technology, to generate bifunctional peptides, capable of non-covalently linking antibiotics to bone, satisfying the unmet need for localized antibiotic delivery to bone tissues. After successfully accomplishing our Phase I aims, we would immediately initiate a Phase II research program, testing the efficacy of this peptide-mediated delivery system in vivo, and designing peptides targeting other therapeutics, such as hematopoietic agents, osteoporosis inhibitors and osteogenic factors for localized bone delivery.